1. Field of the Invention
The present invention relates to unique oral dosage formulations of l-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea, a pharmacological agent exhibiting novel anti-inflammatory activity. More particularly, the present invention relates to oral dosage formulations of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea that provide enhanced stability of the compound in ionic environments, improved solubility, and/or improved oral bioavailability, and are produced using unique process conditions.
2. Background of the Related Art
1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea (hereinafter, xe2x80x9cBIRB 796xe2x80x9d) is disclosed in commonly assigned co-pending PCT Application No. PCT/US99129165, herein incorporated by reference, as 
possessing unexpectedly significant inhibitory activity with respect to proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). BIRB 796 has implications for the treatment of numerous disease states including arthritis, psoriasis and Crohn""s disease. While having many advantageous pharmacological properties, BIRB 796 has been found to possess certain less than desirable pharmaceutical properties, including poor aqueous solubility, poor powder flow properties, and a tendency to discolor in the presence of light.
At least seven polymorphs of BIRB 796 have been isolated (the melt point of the drug is about 152xc2x0 C. and the pKa about 6.1). The polymorphs generally exist in the form of elongated needles. BIRB 796 is relatively poorly soluble in physiological environments. The solubility of polymorphic BIRB 796 drug substance (Form IV) has been determined to be about 0.5 ug/ml at pH 7.4 and about 10 mg/ml at pH 2.0.
BIRB 796 may be administered by the many routes of administration known in the art, including, but not limited to, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, bucally, rectally, aurally, ocularly, transdermally, etc. A preferred route of administration is oral administration by way of, for example, tablets, capsules, caplets, troches, lozenges, powder, cachets, solutions and suspensions. Core tablets may be prepared by addition of excipient, binder, disintegrant, lubricant and so on, as would be understood by one of ordinary skill in the art. Core tablets containing BIRB 796 may be subjected to surface coating with a main coating agent such as, but not limited to, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxypropyl cellulose and the like. Formulations have been prepared which deliver doses from 0.5 mg to 300 mg.
The present inventors have recently discovered that the solubility of BIRB 796 is adversely diminished when in the presence of ionic solutions. Increasing ionic strength has been found to result in an overall decrease in the dissolution of BIRB 796. As the various parts of the human (and other mammalian) intestinal tract show considerable variability in ionic strength (typically ranging from I=0.15-0.40 M), and as the ionic strength of the intestinal tract may be significantly affected by intake of certain pharmaceutical products and foodstuffs, this variability of the solubility of BIRB 796 with ionic strength may have significant adverse impacts on the overall bioavailability of BIRB 796.
BIRB 796 formulations have also been discovered to be plagued with less than desirable adherency characteristics. Formulations containing BIRB 796 have been found to suffer from the tendency of materials to stick to compression dies and/or punch faces, as well as to stick to powder conduits, filling tubes, and other processing chambers. Within conventional ranges, increases in the amount of lubricant in the formulation have not been found to be adequate to resolve the problem.
There is a need therefore for formulations of BIRB 796 with improved solubility and diminished adherency characteristics, which provide better oral bioavailability of the drug as well as allow for efficient preparation of dosage forms.
The present invention discloses formulations of BIRB 796, and processes for manufacturing such BIRB 796 formulations, that provide for improved solubilization and/or bioavailability of BIRB 796, and which display improved flow characteristics. In particular, advantageous oral dosage formulations of BIRB 796 are provided.
It has been discovered by the present inventors that the flow properties of BIRB 796 drug substance may be significantly improved (adherence to surfaces reduced), by granulation of the material followed by milling of the dried granules in such a manner so as to form a granular composition of BIRB 796 within a defined range of granule sizesxe2x80x94such that the portion of granules which do not pass through a 1000 micron sieve do not account for more than about 5 percent by weight of the total granules, the amount that do not pass through a 250 micron sieve does not account for more than about 60 percent by weight, and the portion of granules which pass through a 63 micron sieve do not account for more than about 20 percent by weight. Such granular compositions of BIRB 796 have been obtained using a cone mill set at various rpms with a 1000 micron rasp or grate screen. Manual milling through a 1000 micron screen, followed by a 700 micron screen has also been found capable of producing such acceptable sieve patterns.
Surprisingly, it has been determined by the present inventor that BIRB 796 solubility is peculiarly affected by the ionicity of its attendant milieu. In particular, aqueous solubility of BIRB 796 has been found to significantly decrease as the ionic strength of its milieu increases. Decreased dissolution has been found to affect overall bioavailability of drugs.
Presented with numerous possibilities for protecting BIRB 796 from ionic interaction, the present inventor has discovered (after numerous failed attempts) a relatively cheap and effective alteration in formulation that may be made that significantly improves BIRB 796 dissolution in ionic solutions. Such improved formulation includes a pharmaceutically non-toxic, aqueous-soluble, inclusion compound (preferably polymeric in form) that is capable of forming a complex with BIRB 796 via manufacture by wet or dry granulation and in its aqueous state so as to protect BIRB 796 from interaction with ionic species. By inclusion compound it is meant a compound capable of forming a cage structure with an unrelated molecule so as to form a well-defined addition structure (the cage structure being formed by one or more molecules of inclusion compound). A preferred inclusion compound of the present invention contains amylose moieties. A particularly preferred inclusion compound is cyclodextrin. A particularly preferred cyclodextrin is xcex2-cyclodextrin.
When employing beta-cyclodextrin in combination with BIRB 796 to protect against ion-induced diminishment of BIRB 796 solubilization, it is preferred that the beta-cyclodextrin:BIRB 796 weight ratio be at least about 1, more preferably to be at least about 2, and yet more preferably to be at least about 3. Such mixtures have been found to significantly enhance the dissolution of BIRB 796 in aqueous solutions, with the higher beta-cyclodextrin composition generally providing a better overall effect.
Unexpectedly, it further has been discovered that standard techniques for application of coating material to core tablets need to be altered when the core tablet contains significant amounts of a cyclodextrin (greater than about 10%). While coatings are conventionally applied at temperatures of 40xc2x0 C. or above, it has been found that when a compression (i.e. tablets and the like) contains cyclodextrins that the coating temperature must be kept below 40xc2x0 C. in order to prevent chipping and ultimately disintegration of the compression. Such chipping and disintegration problem is particularly noted when the core tablet contains substantial amounts of cyclodextrin (xe2x89xa7 about 40%). In particular, coatings applied to compressions (such as core tablets) containing beta-cyclodextrin need to be applied at temperatures below 40xc2x0 C., more preferably below 39xc2x0 C., temperatures above 40xc2x0 C. causing chipping and disintegration of the compression.
The addition of cyclodextrin inclusion compounds to the BIRB 796 oral formulation was seen to improve the average total plasma concentration of BIRB 796 (in dogs) over a twelve hour period (AUC0-12), as well as the maximum plasma concentration (Cmax) attained as compared to formulations containing lactose. The time to maximum concentration (Tmax) was also seen to be reduced as compared to lactose formulations lacking cyclodextrin.
One aspect of the present invention consists of a pharmaceutical oral dosage form comprsing: (a) a pharmaceutically effective dose of BIRB 796; and (b) a pharmaceutically non-toxic amount of an aqueous soluble inclusion compound that is capable of forming a complex with BIRB 796 in its aqueous state so as to substantially protect BIRB 796 from interaction with ionic species.
In another embodiment of the present invention, there is disclosed pharmaceutical tablet comprising: (a) a homogenous core comprising granulated BIRB 796 and a cyclodextrin; and (b) a coating completely covering said homogenous core which comprises any suitable coating, and preferably a water dispersible pharmaceutically-acceptable polymer coating, or the like.
In yet another embodiment of the present invention, there is disclosed a pharmaceutical tablet comprising: (a) between about 0.1 to about 35% by weight granulated BIRB 796; (b) between about 25 to about 50% by weight binding agent; (c) between about 3 to about 40% by weight disintegrant; and (d) between about 25 to about 60% by weight soluble granulation aid.